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Unveiling an 'invisible' gut virus

A newly-discovered virus lives inside our stomach bacteria and may be linked to obesity. Dyani Lewis charts the detective work that led to its discovery.

Bacteriophages, like the one shown here, parasitise gut bacteria but most are virtually invisible. New DNA techniques have shone the spotlight on an abundant new variety that may play a role in gut health. – SPL Creative/GETTY IMAGES

Jonathan Swift observed that “a flea hath smaller fleas that on him prey. And these have smaller fleas to bite 'em. And so proceeds Ad infinitum”.

Perhaps the 17th century writer was imagining something like the viruses that parasitise bacteria, also called “bacteriophages” – literally bacteria-eaters. Large quantities of a newly discovered bacteriophage have been found living in bacteria that colonise the human gut. It may be a parasite but because it is present at such high levels some researchers speculate it might instead help the metabolism of the bacterium. The type of bacteria it probably infects, the genus Bacteroides, has also been linked with obesity and related diseases suggesting the virus may also indirectly play a role in human health.

Recent years have uncovered the microbiome – the universe of our co-habiting bacteria that outnumber our cells by ten to one. Just which types of bacteria we harbour are linked to health and disease. But what has remained a largely hidden world is the population of viruses that infect these bacteria.

The new virus, named crAssphage, was found by an international research team based at San Diego State University. The discovery, published in Nature Communications in July, involved some clever computational detective work by lead author Bas Dutilh, now at Radboud University Medical Centre in the Netherlands. Dutilh detected crAssphage in fragments of DNA extracted from human faecal samples without ever seeing it under the microscope. He used his program, “crAss”, to piece it together – hence the name. It may be hard to see but the virus is widespread and plentiful. Dutilh and his team found crAssphage DNA in about three quarters of faecal samples from around the world. And in one sample from a person in South Korea crAssphage accounted for 24% of the viral DNA present.

Until recently the microbial communities that colonise our bodies have largely been invisible because they are very fussy about the conditions they live in and refuse to reveal themselves by growing in petri dishes in the lab. But recent DNA-sequencing technologies have put the spotlight on once-hidden microbial communities. Scientists read their DNA signatures in skin swabs or faecal samples and then cross-check the signatures against vast databases to obtain their identities.

The virus may be helpful both to its bacterial host andto its host’s host – humans.

Part of the problem with this approach is that you can only identify microbes if they have already been described in the databases. “You can sequence everything, but if it doesn't look like anything identifiable, people have just been throwing away a lot of the data, says microbiologist Martha Clokie from the University of Leicester.

To get around this prejudice for known organisms Dutilh developed a new method that ignored the databases. He focused on the thousands of fragments of viral DNA contained in just 12 faecal samples and wrote a computer program that sifted through their sequences. The program connected sequences that overlapped, gradually building up larger and larger strings of DNA like completing a jig-saw puzzle, until an entire viral genome emerged. “Metagenomics is sequencing DNA from anything that's out there and you should let the unknown speak for itself,” says Dutilh.

“It’s a very clever approach and very powerful,” says Josefa Antón Botella from the University of Alicante in Spain, who plans to use the new approach to look at microbial samples in her own lab.

Once the team had assembled a complete viral genome they then turned to the databases. It turns out a lot of previously unknown virus signatures were that of crAssphage, showing how common it is. This was also a surprise, says Dutilh. Researchers had previously assumed that the viruses in one person would bear little resemblance to the viruses in another person because they evolve so rapidly. But with crAssphage cropping up in samples from South Korea to the US and Europe it now seems that some viruses evolve far more slowly.

With further detective work Dutilh predicted that crAssphage probably infects a species of Bacteroides, a type of bacterium common in the human gut. Amounts of the virus in different samples correlate with amounts of the bacterium and DNA that matches the virus has been found associated with Bacteroides DNA.

Dutilh speculates that instead of being a parasite crAssphage could be providing its host with useful metabolic functions for life in the gut. Even though bacteriophages are usually a bacterium’s worst nightmare - bacteria usually burst after infection - occasionally they do strike up a partnership. For instance some bacteria can acquire antibiotic resistance genes from a phage.

But in this case the virus may be helpful both to its bacterial host and to its host’s host humans. Studies have revealed stark differences in the make-up of gut microbial communities in healthy versus unhealthy people. Some strains of Bacteroides seem to be associated with being slimmer, according to recent research in mice, but studies in people suggest it may have the opposite effect in humans. The jury is still out.

The work also highlights how little is known about the viruses that infect bacteria, says Dutilh, “There’s a lot more out there.”